On the causes of rising gross ecosystem productivity in a regenerating clearcut environment: leaf area vs. species composition.
Clearcutting a forest ecosystem can result in a drastic reduction of stand productivity. Despite the severity of this disturbance type, past studies have found that the productivity of young regenerating stands can quickly rebound, approaching that of mature undisturbed stands within a few years. One of the obvious reasons is increased leaf area (LA) with each year of recovery. However, a less obvious reason may be the variability in species composition and distribution during the natural regeneration process. The purpose of this study was to investigate to what extent the increase in gross ecosystem productivity (GEP), observed during the first 4 years of recovery in a naturally regenerating clearcut stand, was due to (i) an overall expansion of leaf area and (ii) an increase in the canopy's photosynthetic capacity stemming from either species compositional shifts or drift in physiological traits within species. We found that the multi-year rise in GEP following harvest was clearly attributed to the expansion of LA rather than a change in vegetation composition. Sizeable changes in the relative abundance of species were masked by remarkably similar leaf physiological attributes for a range of vegetation types present in this early-successional environment. Comparison of upscaled leaf-chamber estimates with eddy-covariance-based estimates of light-response curves revealed a broad consistency in both maximum photosynthetic capacity and quantum yield efficiency. The approaches presented here illustrate how chamber- and ecosystem-scale measurements of gas exchange can be blended with species-level LA data to draw conclusive inferences about changes in ecosystem processes over time in a highly dynamic environment.


The importance of psychological factors in the maintenance of oral health: a study of Swedish university students.
The aim of this study was to investigate the predictive value of the traditional multidimensional health locus of control (MHLC) scale, a corresponding dental health locus of control (DHLC) scale and dental health values (DHVs) regarding students' dental health before and after a video programme that presented information about dental diseases and instructions on oral hygiene. A group of 217 university students participated in this study. Before the video programme was presented, assessments were made of MHLC, DHLC and DHVs. Plaque and gingival indices were obtained in a clinical examination conducted before (plaque index [PLI] 1 and gingival index [GI] 1) and 10 weeks after (PLI 2 and GI 2) the presentation of the programme. The percentage of tooth surfaces exhibiting plaque and of sites involving gingivitis decreased and was statistically significant between baseline and re-examination for both males and females. The females exhibited statistically significant better PLI 1 and GI 1 values and stronger DHVs than males. Also, better GI 1 values were found to be statistically significant and related to stronger DHVs for females. A stronger trust in the dental health personnel regarding the dental health was related to more gingivitis at the initial examination (GI 1). For males, stronger internal DHLC was related to more plaque at the final examination (PLI 2). The only psychological scales that showed some relationship to the measures of dental health were DHLC and DHVs. Gender was the strongest related variable to dental health.


Studies on the mechanism of action of dioctyl sodium sulphosuccinate in the human jejunum.
An intestinal perfusion technique has been used to investigate the mechanism of action of the laxative, dioctyl sodium sulphosuccinate, in the human jejunum. Dioctyl sodium sulphosuccinate stimulated net secretion of water, sodium, chloride and potassium and inhibited net absorption of glucose and bicarbonate. These changes in water and solute transport were partially reversed by administration of indomethacin (4 mg/kg/day orally for three days), which suggests that they are mediated in part by endogenous prostaglandins.


Is there any relation between connective tissue growth factor and scar tissue in vesicoureteral reflux?
Gültekin ND, Benzer M, Tekin-Neijmann Ş. Is there any relation between connective tissue growth factor and scar tissue in vesicoureteral reflux. Turk J Pediatr 2019; 61: 71-78. Vesicoureteral reflux (VUR) is the most common uropathy in childhood which leads to increased frequency of urinary tract infection (UTI) and renal scarring. Connective tissue growth factor (CTGF) plays an important role in the development of glomerular and tubulointerstitial fibrosis in progressive kidney diseases. The aim of this study was to investigate the relation between urinary CTGF and renal damage resulted from VUR. This cross sectional study included 70 patients with VUR and 62 healthy sex and age matched children. Urinary creatinine and CTGF (uCTGF) concentrations were analysed in all cases and CTGF to creatinine ratio were calculated. The records of radiologic evaluations of the patients including ultrasound, voiding cystouretrography and 99m-technetium dimercaptosuccinic acid (DMSA) scintigraphy were obtained retrospectively. The patient group was further divided into two groups according to the existence of renal cortical scarring in the DMSA scan. The study consisted of three groups; Group 1 (control group) 62 children, Group 2 (VUR positive, scar negative) 24 patient, Group 3 (VUR positive, scar positive) 46 patient (VUR+scar). The medians of uCTGF and uCTGF to creatinine ratio of the three groups were significantly different (p < 0.001). Pairwise group comparisons revealed that Group 1 had significantly lower uCTGF level and uCTGF/creatinine ratio, as compared to Groups 2 and 3 (p < 0.001 and p=0.002, respectively). There was no statistically significant difference between Groups 2 and 3 (p=0.052). uCTGF is significantly increased in children with VUR, independent on the presence of renal scarring. Increased uCTGF, even in the absence of the renal scarring, could be interpreted as development and a progression of glomerular and tubulointerstitial fibrosis in vesicoureteral reflux. Further experimental and clinical investigations are required to fully elucidate the mechanism of CTGF in vesicoureteral reflux.


Factors contributing to infant overfeeding in low-income immigrant Latina mothers.
Approximately 10% of U.S. infants and toddlers are considered overweight. Hispanic infants persistently show higher prevalence rates for being overweight compared to other infants. Little is known about factors promoting excessive infant weight gain in Latinos. The aim of this study was to describe multidimensional factors and maternal feeding practices that may correlate with infant overfeeding in Latina mothers. Participants were 62 low-income immigrant Latina mothers and their infants. Study measures were: acculturation; maternal feeding beliefs and practices; food availability; temperament; 24-hour dietary recall; and infant's weight-for-height z score. In regression models adjusted for infant's age, healthier feeding practices were significantly predicted by maternal education and infant's age. Most mothers preferred feeding their infants either formula or a combination of breast milk and formula. A significant proportion of the infants were overweight or obese and yet some mothers displayed difficulty recognizing this problem. Future intervention efforts should focus primarily on the promotion of healthy feeding practices that discourage overfeeding and support exclusive breastfeeding among this ethnic group.


Newly discovered deep-branching marine plastid lineages are numerically rare but globally distributed.
Ocean surface warming is resulting in an expansion of stratified, low-nutrient environments, a process referred to as ocean desertification [1]. A challenge for assessing the impact of these changes is the lack of robust baseline information on the biological communities that carry out marine photosynthesis. Phytoplankton perform half of global biological CO2 uptake, fuel marine food chains, and include diverse eukaryotic algae that have photosynthetic organelles (plastids) acquired through multiple evolutionary events [1-3]. While amassing data from ocean ecosystems for the Baselines Initiative (6,177 near full-length 16S rRNA gene sequences and 9.4 million high-quality 16S V1-V2 amplicons) we identified two deep-branching plastid lineages based on 16S rRNA gene data. The two lineages have global distributions, but do not correspond to known phytoplankton. How the newly discovered phytoplankton lineages contribute to food chains and vertical carbon export to the deep sea remains unknown, but their prevalence in expanding, low nutrient surface waters suggests they will have a role in future oceans.


Effect of erythropoiesis-stimulating agents on blood pressure in pre-dialysis patients.
Erythropoiesis-Stimulating Agents (ESA) are hypothesized to increase cardiovascular mortality in patients with chronic kidney disease. One of the proposed mechanisms is the elevation of blood pressure (BP) by ESA. Therefore, we aimed to determine whether the use of ESA was associated with antihypertensive treatment and higher BP. In this cohort 502 incident pre-dialysis patients were included who started specialized pre-dialysis care in 25 clinics in the Netherlands. Data on medication including ESA use and dose, co-morbidities and BP were routinely collected every 6 months. Antihypertensive treatment and BP were compared for patients with and without ESA at baseline. Differences in antihypertensive medication and BP during pre-dialysis care were estimated with linear mixed models adjusted for age, sex, body mass index, cardiovascular disease, diabetes mellitus and estimated glomerular filtration rate. At baseline, 95.6% of patients with ESA were treated with antihypertensive medication and 73.1% of patients without ESA. No relevant difference in BP was found. During pre-dialysis care patients with ESA used 0.77 (95% CI 0.63;0.91) more classes of antihypertensive drugs. The adjusted difference in systolic blood pressure (SBP) was -0.3 (95% CI -2.7;2.0) mmHg and in diastolic blood pressure (DBP) was -1.0 (95% CI -2.1;0.3) mmHg for patients with ESA compared to patients without ESA. Adjusted SBP was 3.7 (95% CI -1.6;9.0) mmHg higher in patients with a high ESA dose compared to patients with a low ESA dose. Our study confirms the hypertensive effect of ESA, since ESA treated patients received more antihypertensive agents. However, no relevant difference in BP was found between patients with and without ESA, thus the increase in BP seems to be controlled for by antihypertensive medication.


Analysis of histones and chromatin in Xenopus laevis egg and oocyte extracts.
Histones are the major protein components of chromatin, the physiological form of the genome in all eukaryotic cells. Chromatin is the substrate of information-directed biological processes, such as gene regulation and transcription, replication, and mitosis. A long-standing experimental model system to study many of these processes is the extract made from the eggs of the anuran Xenopus laevis. Since work in recent years has solidified the importance of post-translational modification of histones in directing biological processes, the study of histones in a biochemically dissectible model such as Xenopus is crucial for the understanding of their biological significance. Here we present a rationale and methods for isolating and studying histones and chromatin in different Xenopus egg and oocyte extracts. In particular, we present protocols for the preparation of: cell-free egg and oocyte extract; nucleoplasmic extract ("NPE"); biochemical purification of maternally-deposited, stored histones in the oocyte and the egg; assembly of pronuclei in egg extract and the isolation of pronuclear chromatin and histones; and an extract chromatin assembly assay. We also demonstrate aspects of the variability of the system to be mindful of when working with extract and the importance of proper laboratory temperature in preparing quality extracts. We expect that these methods will be of use in promoting further understanding of embryonic chromatin in a unique experimental system.


Process optimization via response surface methodology in the treatment of metal working industry wastewater with electrocoagulation.
In this study, process parameters in chemical oxygen demand (COD) and turbidity removal from metal working industry (MWI) wastewater were optimized by electrocoagulation (EC) using aluminum, iron and steel electrodes. The effects of process variables on COD and turbidity were investigated by developing a mathematical model using central composite design method, which is one of the response surface methodologies. Variance analysis was conducted to identify the interaction between process variables and model responses and the optimum conditions for the COD and turbidity removal. Second-order regression models were developed via the Statgraphics Centurion XVI.I software program to predict COD and turbidity removal efficiencies. Under the optimum conditions, removal efficiencies obtained from aluminum electrodes were found to be 76.72% for COD and 99.97% for turbidity, while the removal efficiencies obtained from iron electrodes were found to be 76.55% for COD and 99.9% for turbidity and the removal efficiencies obtained from steel electrodes were found to be 65.75% for COD and 99.25% for turbidity. Operational costs at optimum conditions were found to be 4.83, 1.91 and 2.91 €/m3 for aluminum, iron and steel electrodes, respectively. Iron electrode was found to be more suitable for MWI wastewater treatment in terms of operational cost and treatment efficiency.


Safety and tolerability of a live oral Salmonella typhimurium vaccine candidate in SIV-infected nonhuman primates.
Nontyphoidal Salmonella (NTS) serovars are a common cause of acute food-borne gastroenteritis worldwide and can cause invasive systemic disease in young infants, the elderly, and immunocompromised hosts, accompanied by high case fatality. Vaccination against invasive NTS disease is warranted where the disease incidence and mortality are high and multidrug resistance is prevalent, as in sub-Saharan Africa. Live-attenuated vaccines that mimic natural infection constitute one strategy to elicit protection. However, they must particularly be shown to be adequately attenuated for consideration of immunocompromised subjects. Accordingly, we examined the safety and tolerability of an oral live attenuated Salmonella typhimurium vaccine candidate, CVD 1921, in an established chronic simian immunodeficiency virus (SIV)-infected rhesus macaque model. We evaluated clinical parameters, histopathology, and measured differences in mucosal permeability to wild-type and vaccine strains. Compared to the wild-type S. typhimurium strain I77 in both SIV-infected and SIV-uninfected nonhuman primate hosts, this live-attenuated vaccine shows reduced shedding and systemic spread, exhibits limited pathological disease manifestations in the digestive tract, and induces low levels of cellular infiltration in tissues. Furthermore, wild-type S. typhimurium induces increased intestinal epithelial damage and permeability, with infiltration of neutrophils and macrophages in both SIV-infected and SIV-uninfected nonhuman primates compared to the vaccine strain. Based on shedding, systemic spread, and histopathology, the live-attenuated S. typhimurium strain CVD 1921 appears to be safe and well-tolerated in the nonhuman primate model, including chronically SIV-infected rhesus macaques.


Use of polyelectrolyte complexes and multilayers from polymers and nanoparticles to create sacrificial bonds between surfaces.
In this study, particle polyelectrolyte complexes (PPECs) were formed by mixing cationic polyacrylamide (CPAM) and silica nanoparticles using the jet mixing technique. Within certain limits, the size of the formed PPECs could be controlled. The aim was to prepare PPECs with embedded sacrificial bonds, similar to those found in bones. Examination of PPEC adsorption to silica model surfaces indicated that smaller PPECs adsorbed to a higher level than larger ones, due to the higher diffusion speed of smaller complexes. Adsorption studies of the same components as in the PPECs, but arranged in multilayers, that is, particle polyelectrolyte multilayers (PPEMs), indicated a stable, gradual build-up of material on the surface with smaller nanoparticles, whereas PPEMs comprising elongated nanoparticles appeared to be more loosely adsorbed onto the surface when the nanoparticles were in the outer layer, due to repulsive forces within the adsorbed layer. The AFM colloidal probe technique was used to study the interaction between surfaces treated with PPECs, multilayers, or polyelectrolyte complexes (PECs). The results showed that the expected long-range disentanglement could be achieved with PPECs but that the pull-off forces were generally low. Treatment with PPEMs comprising the same polymer and nanoparticle components produced higher pull-off values, together with disentanglement behaviour, possibly due to better contact between the surfaces. Adhesion experiments with polymer PECs showed significantly higher pull-off values than with the PPECs, probably due to polymer interdiffusion across the surface boundary.


Dioxin cancer risk--example of hormesis?
A recent case-control study implied an inverse correlation between the measured body burden of dioxins (polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans, PCDD/F) and the risk of soft tissue sarcoma in normal population exposed to dioxins mainly via food. The surprising result could not be explained by biases or confounding. There is no a priori confounding by occupational chemicals in a random sample from general population, but exposures to other lipid soluble chemicals with similar sources might be expected to associate with that of dioxins. One such group is polychlorinated biphenyls (PCB). Therefore three most relevant dioxin-like PCB compounds PCB 77, PCB 126, and PCB 169 were now analyzed from the same patients. Cases were 110 soft-tissue sarcoma patients undergoing surgery for their disease, and referents were 227 patients operated for appendicitis. Dioxin and PCB concentrations were analyzed from subcutaneous fat samples by high-resolution gas chromatography-mass spectrometry and TCDD equivalent concentrations (WHO-TEq) were calculated by using toxicity equivalency factors of WHO. The highest risk of sarcoma was found in the septile with the lowest body burden of sum WHO-TEq, and the differences of septiles 2 and 6 from septile 1 were statistically significant. If soft sarcoma risk is true at high occupational levels of dioxins, the provocative result suggests that a possibility of a J-shaped dose-response curve should be taken into consideration and studied further. This is also supported by the similar J-shaped dose responses in animal studies.


A new sensitive and accurate model to predict moderate to severe obstructive sleep apnea in patients with obesity.
Obstructive sleep apnea (OSA) has a high prevalence in patients with obesity. Only patients with clinical symptoms of OSA are admitted to polysomnography; however, many patients with OSA are asymptomatic. We aimed to create and validate a population-based risk score that predicts the severity of OSA in patients with obesity.We here report the cross-sectional analysis at baseline of an ongoing study investigating the long-term effect of bariatric surgery on OSA. One-hundred sixty-one patients of the Obesity Center of the Catholic University Hospital in Rome, Italy were included in the study. The patients underwent overnight cardiorespiratory monitoring, blood chemistry analyses, hepatic ultrasound, and anthropometric measurements. The patients were divided into 2 groups according OSA severity assessed by the apnea-hypopnea index (AHI): AHI < 15 = no or mild and AHI ≥ 15 moderate to severe OSA. A statistical prediction model was created and validated. C statistics was used to evaluate the discrimination performance of the model.The prevalence of OSA was 96.3% with 74.5% of the subjects having moderate/severe OSA. Sex, body mass index, diabetes, and age were included in the final prediction model that had excellent discrimination ability (C statistics equals to 83%). An OSA risk chart score for clinical use was created.Patients with severe obesity are at a very high risk for moderate or severe OSA in particular if they are men, older, more obese, and/or with type 2 diabetes. The OSA risk chart can be useful for general practitioners and patients as well as for bariatric surgeons to select patients with high risk of moderate to severe OSA for further polysomnography.


Rapid report: postsynaptic bursting is essential for 'Hebbian' induction of associative long-term potentiation at excitatory synapses in rat hippocampus.
1. The biologically relevant rules of synaptic potentiation were investigated in hippocampal slices from adult rat by mimicking neuronal activity seen during learning behaviours. Synaptic efficacy was monitored in two separate afferent pathways among the Schaffer collaterals during intracellular recording of CA1 pyramidal neurones. The effects of pairing presynaptic single spikes or bursts with postsynaptic single spikes or bursts, repeated at 5 Hz ('theta' frequency), were compared. 2. The pairing of ten single evoked excitatory synaptic events with ten postsynaptic single action potentials at 5 Hz, repeated twelve times, failed to induce synaptic enhancement (EPSP amplitude 95% of baseline amplitude 20 min after pairing; n = 5). In contrast, pairing the same number of action potentials, but clustered in bursts, induced robust synaptic potentiation (EPSP amplitude 163%; P < 0.01, Student's t test; n = 5). This potentiation was input specific, long lasting ( > 1 h; n = 3) and its induction was blocked by an antagonist at NMDA receptors (20-50 microM D(-)-2-amino-5-phosphonopentanoic acid; EPSP amplitude 109%; n = 6). 3. Presynaptic bursting paired with postsynaptic single action potentials did not induce input specific synaptic change (113 % in the test input vs. 111 % in the control; n = 8). In contrast, postsynaptic bursting when paired with presynaptic single action potentials was sufficient to induce synaptic potentiation when the presynaptic activity preceded the postsynaptic activity by 10 ms (150 vs. 84 % in the control input; P < 0.01; n = 10). 4. These results indicate that, under our conditions, postsynaptic bursting activity is necessary for associative synaptic potentiation at CA1 excitatory synapses in adult hippocampus. The existence of a distinct postsynaptic signal for induction of synaptic change calls for refinement of the common interpretation of Hebb's rule, and is likely to have important implications for our understanding of cortical network operation.


Slit-Robo signalling in heart development.
The Slit ligands and their Robo receptors are well-known for their roles during axon guidance in the central nervous system but are still relatively unknown in the cardiac field. However, data from different animal models suggest a broad involvement of the pathway in many aspects of heart development, from cardiac cell migration and alignment, lumen formation, chamber formation, to the formation of the ventricular septum, semilunar and atrioventricular valves, caval veins, and pericardium. Absence of one or more of the genes in the pathway results in defects ranging from bicuspid aortic valves to ventricular septal defects and abnormal venous connections to the heart. Congenital heart defects are the most common congenital malformations found in life new-born babies and progress in methods for large scale human genetic testing has significantly enhanced the identification of new causative genes involved in human congenital heart disease. Recently, loss of function variants in ROBO1 have also been linked to ventricular septal defects and tetralogy of Fallot in patients. Here, we will give an overview of the role of the Slit-Robo signalling pathway in Drosophila, zebrafish, and mouse heart development. The extent of these data warrant further attention on the SLIT-ROBO signalling pathway as a candidate for an array of human congenital heart defects.


Functional cortical and subcortical abnormalities in pedophilia: a combined study using a choice reaction time task and fMRI.
Pedophiles show sexual interest in prepubescent children but not in adults. Research into the neurofunctional mechanisms of paraphilias has gathered momentum over the last years. To elucidate the underlying neural processing of sexual interest among pedophiles and to highlight the differences in comparison with nonparaphilic sexual interest in adults. Nine pedophilic patients and 11 nonpedophilic control subjects underwent functional magnetic resonance imaging (fMRI) while viewing pictures of nude (prepubescents, pubescents, and adults) and neutral content, as well as performing a concomitant choice reaction time task (CRTT). Brain blood oxygen level-dependent (BOLD) signals and response latencies in the CRTT during exposure to each picture category. Analysis of behavioral data showed group differences in reaction times regarding prepubescent and adult but not pubescent stimuli. During stimulation with pictures displaying nude prepubescents, pedophiles showed increased BOLD response in brain areas known to be involved in processing of visual sexual stimuli. Comparison of pedophilic patients with the control group discovered differences in BOLD responses with respect to prepubescent and adult but not to pubescent stimuli. Differential effects in particular occurred in the cingulate gyrus and insular region. The brain response of pedophiles to visual sexual stimulation by images of nude prepubescents is comparable with previously described neural patterns of sexual processing in nonpedophilic human males evoked by visual stimuli depicting nude adults. Nevertheless, group differences found in the cingulate gyrus and the insular region suggest an important role of these brain areas in pedophilic sexual interest. Furthermore, combining attention-based methods like CRTT with fMRI may be a viable option for future diagnostic procedures regarding pedophilia.


Assessment of corneal biomechanical properties and intraocular pressure in myopic spanish healthy population.
Purpose. To examine biomechanical parameters of the cornea in myopic eyes and their relationship with the degree of myopia in a western healthy population. Methods. Corneal hysteresis (CH), corneal resistance factor (CRF), Goldmann correlated intraocular pressure (IOP), and corneal compensated IOP (IOPcc) were measured using the ocular response analyzer (ORA) in 312 eyes of 177 Spanish subjects aged between 20 and 56 years. Refraction was expressed as spherical equivalent (SE), which ranged from 0 to -16.50 diopters (D) (mean: -3.88 ± 2.90 D). Subjects were divided into four groups according to their refractive status: group 1 or control group: emmetropia (-0.50 ≤ SE < 0.50); group 2: low myopia (-0.75 ≤ SE < 3.00 D); group 3: moderate myopia (-3.00 ≤ SE ≤ -6.00 D); and group 3: high myopia (SE greater than -6.00 D). We analyzed the relationship between corneal biomechanics measured with ORA and SE. Results. CH in the emmetropia, low myopia, moderate myopia, and high myopia groups was 11.13 ± 0.98, 11.49 ± 1.25, 10.52 ± 1.54, and 10.35 ± 1.33 mmHg, respectively. CH in the highly myopic group was significantly lower than that in the emmetropic group (P = 0.07) and low myopic group (P = 0.035); however, there were no differences with the moderate myopic group (P = 0.872). There were no statistically significant differences regarding IOP among the four groups (P > 0.05); nevertheless, IOPcc was significantly higher in the moderately myopic (15.47 ± 2.47 mmHg) and highly myopic (16.14 ± 2.59 mmHg) groups than in the emmetropia (15.15 ± 2.06 mmHg) and low myopia groups (14.53 ± 2.37 mmHg). No correlation between age and the measured parameters was found. CH and IOPcc were weakly but significantly correlated with SE (r = 0.171, P = 0.002 and r = -0.131, P = 0.021, resp.). Conclusions. Present study showed only a very weak, but significant, correlation between CH and refractive error, with CH being lower in both moderately and highly myopic eyes than that in the emmetropic and low myopic eyes. These changes in biomechanical properties of the cornea may have an impact on IOP measurement, increasing the risk of glaucoma.


Recurrent promoter mutations in melanoma are defined by an extended context-specific mutational signature.
Sequencing of whole tumor genomes holds the promise of revealing functional somatic regulatory mutations, such as those described in the TERT promoter. Recurrent promoter mutations have been identified in many additional genes and appear to be particularly common in melanoma, but convincing functional data such as influence on gene expression has been more elusive. Here, we show that frequently recurring promoter mutations in melanoma occur almost exclusively at cytosines flanked by a distinct sequence signature, TTCCG, with TERT as a notable exception. In active, but not inactive, promoters, mutation frequencies for cytosines at the 5' end of this ETS-like motif were considerably higher than expected based on a UV trinucleotide mutational signature. Additional analyses solidify this pattern as an extended context-specific mutational signature that mediates an exceptional position-specific vulnerability to UV mutagenesis, arguing against positive selection. We further use ultra-sensitive amplicon sequencing to demonstrate that cell cultures exposed to UV light quickly develop subclonal mutations specifically in affected positions. Our findings have implications for the interpretation of somatic mutations in regulatory regions, and underscore the importance of genomic context and extended sequence patterns to accurately describe mutational signatures in cancer.


Minimal access surgery for repair of congenital diaphragmatic hernia: is it advantageous?--An open review.
Congenital diaphragmatic hernia (CDH) is a congenital life-threatening condition requiring surgical repair in the neonatal period. Minimal access surgery (MAS) is gaining ground on the classical open approach by laparotomy or thoracotomy as it minimizes damage to the abdominal or thoracic wall. Using an open review of the literature, we aimed to determine whether MAS is safe and effective in treating CDH. Furthermore, we provide selection criteria for the optimal surgical approach, laid down in a decision algorithm. An online search of MEDLINE was performed (May 2012), followed by a citations search. All study types except case reports describing open and/or MAS repair of Bochdalek CDH were eligible. Primary outcome data, for example, surgical complications and mortality, were recorded, as well as secondary outcome measures, for example, operative time, duration of postoperative ventilation, tolerance of enteral nutrition, and total length of stay (LOS) in hospital. Analysis was performed in accordance with the standards of the Cochrane Handbook for Systematic Reviews of Interventions. We identified 15 relevant studies, 5 of them describing MAS only and 10 comparing MAS to open repair of CDH. Numbers of included patients and selection criteria for MAS varied widely. Most studies have methodological limitations, such as the use of retrospective data or historical control groups. ECMO treatment and patch use were more frequent in the open repair group (both p < 0.0001). Recurrence risk seemed to be increased in the MAS group. The need for conversion in MAS series ranged widely, from 3.4 to 75.0%. The risk of general surgical complications did not vary between groups. Mortality seemed to be less in the MAS group. Operative time seemed to be longer in the MAS group. Duration of postoperative ventilation and total LOS appeared to be reduced in this group and patients returned quicker to enteral nutrition. We demonstrate that MAS for diaphragmatic hernia appears to be safe in terms of complications and mortality. Besides, it is associated with faster postoperative recovery. Growing experience with this technique is expected to lower the recurrence risk and to shorten the operative time. These findings should be interpreted cautiously because of methodological limitations of the studies included. Selection criteria used in various studies are associated with an important risk of selection bias. Nonetheless, these criteria can be used to identify patients who will benefit most from MAS.


Serological Cross-Reactions between Expressed VP2 Proteins from Different Bluetongue Virus Serotypes.
Bluetongue (BT) is a severe and economically important disease of ruminants that is widely distributed around the world, caused by the bluetongue virus (BTV). More than 28 different BTV serotypes have been identified in serum neutralisation tests (SNT), which, along with geographic variants (topotypes) within each serotype, reflect differences in BTV outer-capsid protein VP2. VP2 is the primary target for neutralising antibodies, although the basis for cross-reactions and serological variations between and within BTV serotypes is poorly understood. Recombinant BTV VP2 proteins (rVP2) were expressed in Nicotiana benthamiana, based on sequence data for isolates of thirteen BTV serotypes (primarily from Europe), including three 'novel' serotypes (BTV-25, -26 and -27) and alternative topotypes of four serotypes. Cross-reactions within and between these viruses were explored using rabbit anti-rVP2 sera and post BTV-infection sheep reference-antisera, in I-ELISA (with rVP2 target antigens) and SNT (with reference strains of BTV-1 to -24, -26 and -27). Strong reactions were generally detected with homologous rVP2 proteins or virus strains/serotypes. The sheep antisera were largely serotype-specific in SNT, but more cross-reactive by ELISA. Rabbit antisera were more cross-reactive in SNT, and showed widespread, high titre cross-reactions against homologous and heterologous rVP2 proteins in ELISA. Results were analysed and visualised by antigenic cartography, showing closer relationships in some, but not all cases, between VP2 topotypes within the same serotype, and between serotypes belonging to the same 'VP2 nucleotype'.


Association of depressed cardiac gp130-mediated antiapoptotic pathways with stimulated cardiomyocyte apoptosis in hypertensive patients with heart failure.
To investigate whether the glycoprotein (gp130)-mediated survival pathway, which protects cardiomyocytes from apoptosis, is depressed in left ventricular hypertrophy hypertensive patients with chronic heart failure. Transvenous endomyocardial biopsies were obtained in 52 hypertensive patients with left ventricular hypertrophy: 28 without heart failure and 24 with heart failure. gp130 and gp130-dependent antiapoptotic pathways p42/44 mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt) as well as gp130 agonist cardiotrophin-1 were analyzed by reverse transcriptase-polymerase chain reaction and western blot. Apoptosis was assessed by DNA end-labeling (TUNEL), caspase-3 immunostaining and caspase substrate poly(ADP-ribose) polymerase cleavage. gp130 protein expression (P < 0.05) and p42/44 MAPK and PI3K/Akt activation (P < 0.01) were decreased in heart-failure hypertensive patients compared with nonheart-failure hypertensive individuals. No changes in gp130 mRNA expression were found between the two groups. Cardiotrophin-1 was increased (P < 0.05) at both the mRNA and protein levels in heart-failure hypertensive individuals compared with nonheart-failure hypertensive individuals. Cardiomyocyte apoptosis was increased (P < 0.01) in heart-failure hypertensive individuals compared with nonheart-failure hypertensive individuals. Inverse correlations (P < 0.01) occurred between cardiomyocyte apoptosis and p42/44 MAPK and PI3K/Akt activation in all hypertensive patients. Cardiotrophin-1 correlated inversely (r = -0.554, P < 0.05) with gp130 in all hypertensive individuals. In cultured HL-1 cardiomyocytes, cardiotrophin-1 decreased (P < 0.05) the gp130:phosphorylated gp130 (at Ser782) ratio and increased (P < 0.05) gp130ubiquitination. An association exists between depression of the gp130 cytoprotective pathway and stimulation of cardiomyocyte apoptosis in hypertensive patients that develop heart failure. Whether the excess of cardiotrophin-1 induces ligand-induced receptor down-regulation in these patients requires further study.


Indirect Music Therapy Practice and Skill-Sharing in Dementia Care.
Public interest in the benefits of music for people with dementia has rapidly increased in recent years. In addition to clinical work with clients, music therapists are often required to support and train staff, families, and volunteers and skill-share some music therapeutic skills. Six music therapy researchers from six countries agreed it was timely to organize a roundtable and share their indirect music therapy practice and examples of skill-sharing in dementia care. This article was developed following the roundtable at the World Congress of Music Therapy in 2017 and further discussion among the authors. This process highlighted the diversity and complexity of indirect music therapy practice and skill-sharing, but some common components emerged, including: 1) the importance of making clinical decisions about when direct music therapy is necessary and when indirect music therapy is appropriate, 2) supporting the transition from direct music therapy to indirect music therapy, 3) the value of music therapy skill-sharing in training care home staff, 4) the need for considering potential risks and burdens of indirect music therapy practice, and 5) expanding the role of music therapist and cultivating cross-professional dialogues to support organizational changes. In indirect music therapy practice, a therapist typically works with carers and supporters to strengthen their relationships with people with dementia and help them further develop their self-awareness and sense of competence. However, the ultimate goal of indirect music therapy practice in dementia care remains the wellbeing of people living with dementia.


Epidemiology of HIV infection in the Middle East and North Africa.
The Middle East and North Africa (MENA) region continues to be perceived as a region with very limited HIV epidemiological data, raising many controversies about the status of the epidemic in this part of the world. The objective of this review and synthesis was to address the dearth of strategic interpretable data on HIV in MENA by delineating a data-driven overview of HIV epidemiology in this region. A comprehensive systematic review of HIV, sexually transmitted infections (STIs) and risk behavior studies in MENA, irrespective of design, was undertaken. Sources of data included Medline for peer-reviewed publications, Google Scholar for other scientific literature published in nonindexed local and regional journals, international organizations reports and databases, country-level reports and database including governmental and nongovernmental organizations publications, as well as various other institutional documents. Over 5000 sources of data related to HIV and STIs were identified and reviewed. The quality of data and nature of study designs varied substantially. There was no evidence for a sustainable HIV epidemic in the general population in any of the MENA countries, except possibly for southern Sudan. The general pattern in different countries in MENA points towards emerging epidemics in high-risk populations including injecting drug users, men who have sex with men (MSM) and to a lesser extent female sex workers, with heterogeneity between countries on the relative role of each of these high-risk groups. Exogenous HIV exposures among nationals linked to travel abroad appeared to be the dominant HIV transmission pattern in a few MENA countries with no evidence for much epidemic or endemic transmission. The role of bridging populations in bridging the HIV infection to the general population was found to be very limited. Although they do not provide complete protection against HIV spread, near universal male circumcision and possibly the prevailing sexually conservative cultural norms seemed to have played so far a protective role in slowing and limiting HIV transmission in MENA relative to other regions. If the existing social and epidemiological context remains largely the same, HIV epidemic transmission is likely to remain confined to high-risk populations and their sexual partners, in addition to exogenous exposures. HIV prevention efforts in this region, which continue to be stymied by stigma associated with HIV/AIDS and related risk behaviors, need to be aggressively expanded with a focus on controlling HIV spread along the contours of risk and vulnerability. There is still a window of opportunity to control further HIV transmission among high-risk groups in MENA that, if missed, may entail a health and socioeconomic burden that the region, in large part, is unprepared for.


Restricted feeding with scheduled sucrose access results in an upregulation of the rat dopamine transporter.
Recent studies suggest that the mesoaccumbens dopamine system undergoes neurochemical alterations as a result of restricted feeding conditions with access to sugars. This effect appears to be similar to the neuroadaptation resulting from drugs of abuse and may underlay some pathological feeding behaviors. To further investigate the cellular mechanisms of these alterations, the present study used quantitative autoradiography and in situ hybridization to assess dopamine membrane transporter (DAT) protein density and mRNA expression in restricted-fed and free-fed adult male rats. The restricted feeding regimen consisted of daily limited access to either a normally preferred sucrose solution (0.3 M) or a less preferred chow in a scheduled (i.e., contingent) fashion for 7 days. Restricted-fed rats with the contingent sucrose access lost less body weight, ate more total food, and drank more fluid than free-fed, contingent food, or noncontingent controls. In addition, these animals had selectively higher DAT binding in the nucleus accumbens and ventral tegmental area. This increase in protein binding also was accompanied by an increase in DAT mRNA levels in the ventral tegmental area. In contrast to the restricted-fed groups, no differential effect in DAT regulation was observed across free-fed groups. The observed alteration in behavior and DAT regulation suggest that neuroadaptation in the mesoaccumbens dopamine system develops in response to repeated feeding on palatable foods under dietary constraints. This supports the notion that similar cellular changes may be involved in restrictive eating disorders and bingeing.


Insulin degludec: overview of a novel ultra long-acting basal insulin.
All the basal insulin products currently available have suboptimal pharmacokinetic (PK) properties, with none reliably providing a reproducible and peakless pharmacodynamic (PD) effect that endures over 24 h from once-daily dosing. Insulin degludec is a novel acylated basal insulin with a unique mechanism of protracted absorption involving the formation of a depot of soluble multihexamer chains after subcutaneous injection. PK/PD studies show that insulin degludec has a very long duration of action, with a half-life exceeding 25 h. Once-daily dosing produces a steady-state profile characterized by a near-constant effect, which varies little from injection to injection in a given patient. Clinically, insulin degludec has been shown consistently to carry a lower risk of nocturnal hypoglycaemia than once-daily insulin glargine, in both basal+bolus and basal-only insulin regimens. The constancy of the steady-state profile of insulin degludec also means that day-to-day irregularities at the time of injection have relatively little PD influence, thereby offering the possibility of greater treatment flexibility for patients.


Motivational nondirective resonance breathing versus transcutaneous vagus nerve stimulation in the treatment of fibromyalgia: study protocol for a randomized controlled trial.
Chronic widespread pain (CWP), including fibromyalgia (FM), affects one in every ten adults and is one of the leading causes of sick leave and emotional distress. Due to an unclear etiology and a complex pathophysiology, FM is a condition with few, if any, effective and safe treatments. However, current research within the field of vagal nerve innervation suggests psychophysiological and electrical means by which FM may be treated. This study will investigate the efficacy of two different noninvasive vagal nerve stimulation techniques for the treatment of FM. The study will use a randomized, single-blind, sham-controlled design to investigate the treatment efficacy of motivational nondirective resonance breathing (MNRB™) and transcutaneous vagus nerve stimulation (Nemos® tVNS) on patients diagnosed with FM. Consenting FM patients (N = 112) who are referred to the Department of Pain Management and Research at Oslo University Hospital, in Oslo, Norway, will be randomized into one of four independent groups. Half of these participants (N = 56) will be randomized to either an experimental tVNS group or a sham tVNS group. The other half (N = 56) will be randomized to either an experimental MNRB group or a sham MNRB group. Both active and sham treatment interventions will be delivered twice per day at home, 15 min/morning and 15 min/evening, for a total duration of 2 weeks (14 days). Participants are invited to the clinic twice, once for pre- and once for post-intervention data collection. The primary outcome is changes in photoplethysmography-measured heart rate variability. Secondary outcomes include self-reported pain intensity on a numeric rating scale, changes in pain detection threshold, pain tolerance threshold, and pressure pain limit determined by computerized pressure cuff algometry, blood pressure, and health-related quality of life. The described randomized controlled trial aims to compare the efficacy of two vagal nerve innervation interventions, MNRB and tVNS, on heart rate variability and pain intensity in patients suffering from FM. This project tests a new and potentially effective means of treating a major public and global health concern where prevalence is high, disability is severe, and treatment options are limited. ClinicalTrials.gov NCT03180554 . Registered on August 06, 2017.


Sunitinib-associated pseudothrombocytopenia induced by IgM antibody.
Thrombocytopenia is a well-documented adverse reaction of sunitinib. Thrombocytopenia was observed in a patient with metastatic renal clear-cell carcinoma undergoing sunitinib treatment. Platelet count in an ethylenediaminetetraacetic acid (EDTA) sample was 19 × 10(9)/l. To exclude pseudothrombocytopenia (PTCP), a platelet count in citrate-anticoagulated blood was performed, showing a platelet count of 6 × 10(9)/l. Due to the apparent thrombocytopenia, the patient received platelet concentrates. Subsequent analyses revealed PTCP whereby platelet clumping was most abundant in citrate - followed by EDTA- and heparin-anticoagulated blood samples. This effect was partially reversed after placing blood samples at 37°C. The IgM antiplatelet autoantibodies responsible for in vitro agglutination are temperature and multianticoagulant dependent and did not react to amikacin pre-supplementation. Remarkably, the antibody revealed specificity to platelet antigens other than GPIIb/IIIa, GPIb/IX, GPIa/IIa, GPIV, and GPV. After 16 days of discontinuing sunitinib, no PTCP and no platelet reactive antibodies could be detected. We report a case of PTCP with clear time-relation with sunitinib, strongly suggesting the mechanism to be sunitinib dependent. Since this finding has not been described before, non-recognition of PTCP during sunitinib treatment might lead to dose reduction or unwarranted therapy.


[Views on the new psychiatric specialist certification system from the perspective of those experiencing the postgraduate psychiatric training system in Japan].
The psychiatric specialist certification system of the Japanese Society of Psychiatry and Neurology was established in 2005, with a transitional period that ran until 2008. A three-year postgraduate training scheme was started in connection with the new psychiatric specialist certification system, and the first formal examination under the new system was held in 2010. A resident desiring certification as a psychiatric specialist must purchase a psychiatric specialist certification handbook and present it when taking the examination. There are many differences between the new examination and the transitional period examination, in terms of both the handbook and the number of case reports to be submitted. Results of a survey conducted on 360 psychiatrists belonging to either university or national hospitals, all of whom had undergone psychiatric training within the past eight years, revealed that there was currently a lack of knowledge, and low rate of utilization, of the handbook. The primary author was in the first cohort of those who began postgraduate psychiatric training in a university hospital and subsequently took the first examination administered after the transition period. The author has maintained that, based on personal experience, a number of issues need improvement, such as the large number of grading items to be signed off on by supervising psychiatrists, and complications involving the outline of cases to be experienced. Additionally, it was thought to be difficult for supervisors who had obtained their specialist certification via the transitional period examination to have an adequate understanding of the outline of the new examination. Therefore, it is important that residents themselves take a more assertive attitude to becoming specialists. In the future, in order to establish a sound specialist certification system, the results of this survey of physicians who took the new examination should be taken into account.


Introduction of ROSA robotic-arm system for total knee arthroplasty is associated with a minimal learning curve for operative time.
The introduction of robotics for total knee arthroplasty (TKA) into the operating theatre is often associated with a learning curve and is potentially associated with additional complications. The purpose of this study was to determine the learning curve of robotic-assisted (RA) TKA within a multi-surgeon team. This prospective cohort study included 83 consecutive conventional jig-based TKAs compared with 53 RA TKAs using the Robotic Surgical Assistant (ROSA) system (Zimmer Biomet, Warsaw, Indiana, USA) for knee osteoarthritis performed by three high-volume (> 100 TKA per year) orthopaedic surgeons. Baseline characteristics including age, BMI, sex and pre-operative Kellgren-Lawrence graded and Hip-Knee-Ankle Axis were well-matched between the conventional and RA TKA groups. Cumulative summation (CUSUM) analysis was used to assess learning curves for operative times for each surgeon. Peri-operative and delayed complications (infection, periprosthetic fracture, thromboembolism, and compromised wound healing) and revisions were reviewed. The CUSUM analysis for operative time demonstrated an inflexion point after 5, 6 and 15 cases for each of the three surgeons, or 8.7 cases on average. There were no significant differences (p = 0.53) in operative times between the RA TKA learning (before inflexion point) and proficiency (after inflexion point) phases. Similarly, the operative times of the RA TKA group did not differ significantly (p = 0.92) from the conventional TKA group. There was no discernible learning curve for the accuracy of component planning using the RA TKA system. The average length of post-operative follow-up was 21.3 ± 9.0 months. There was one revision for instability in the conventional TKA group and none in the RA TKA group. There were no significant difference (p > 0.99) in post-operative complication rates between the conventional TKA and RA TKA groups. The introduction of the RA TKA system was associated with a learning curve for operative time of 8.7 cases. Operative times between the RA TKA and conventional TKA group were similar. The short learning curve implies this RA TKA system can be adopted relatively quickly into a surgical team with minimal risks to patients.


Adipokines, inflammation, and visceral adiposity across the menopausal transition: a prospective study.
Postmenopausal women have greater visceral adiposity compared with premenopausal women. Adipokines are associated with increased adiposity, insulin resistance, and atherosclerosis. The objective of the study was to assess changes in adipokines and inflammatory markers through the menopausal transition and correlate them with changes in visceral adiposity. This was a prospective cohort study of women through the menopausal transition conducted at the University of Washington. Sixty-nine healthy women were followed up longitudinally from premenopausal (aged 45-55 yr) to postmenopausal status (aged 49-60 yr). On premenopausal and postmenopausal visits, fasting blood was drawn for adiponectin, leptin, serum amyloid A (SAA), C-reactive protein (CRP), monocyte-chemotactic protein-1, tissue plasminogen activator antigen (tPA), IL-6, and TNF-alpha. Body composition measures were assessed by body mass index, whole-body dual x-ray absorptiometry scan, and computed tomography scan of the abdomen at the lumbar 4-5 level. Women had a statistically significant increase in SAA, tPA, monocyte-chemotactic protein-1, and adiponectin between the two measurement occasions (P = 0.04, P = 0.02, P = 0.001, and P < 0.001, respectively). The increase in intraabdominal fat was correlated positively with the change in SAA (r = 0.31, P = 0.02), CRP (r = 0.56, P < 0.001), tPA (r = 0.40, P = 0.002), and leptin (r = 0.41, P = 0.002) and negatively correlated with the change in adiponectin (r = -0.37, P = 0.005). After adjustment for change in sc abdominal fat, the correlation between change in CRP, tPA, leptin, and adiponectin remained significantly associated with change in intraabdominal fat. Women going through the menopausal transition have deleterious changes in inflammatory markers and adipokines that correlate with increased visceral adiposity.


Urinary Hydroxyproline Is Only Suitable As a Biomarker for Acute Intake, Up to 6 hr Postingestion of Collagen Proteins in "Free-Living," Healthy, Active Males.
The urinary excretion of hydroxyproline (Hyp), abundant in collagen protein, may serve as a biomarker of habitual collagen intake, assisting with investigations of current interest in the role of dietary collagen intake in supporting the synthesis of collagenous body tissues. This study investigated the time course of urinary Hyp excretion in "free-living," healthy, active males following the ingestion of a standardized bolus (20 g) of collagenous (gelatin and a hydrolyzed collagen powder) and dairy (calcium caseinate and hydrolyzed casein) proteins. The excretion of Hyp was assessed over a 24-hr period, separated into three collection periods: 0-6, 6-12, and 12-24 hr. Hyp was elevated for 0-6 hr after the consumption of collagen-containing supplements (gelatin 31.3 ± 8.8 mmol/mol and hydrolyzed collagen 33.7 ± 22.0 mmol/mol vs. baseline: gelatin 2.4 ± 1.7 mmol/mol and hydrolyzed collagen 2.8 ± 1.5 mmol/mol; p < .05), but not for the dairy protein supplements (calcium caseinate 3.4 ± 1.7 mmol/mol and hydrolyzed casein 4.0 ± 3.7 mmol/mol; p > .05). Therefore, urinary Hyp reflects an acute intake of collagenous protein, but is not suitable as a biomarker for quantifying habitual collagen intake, provided through regular dietary practices in "free-living," healthy, active males.


Probing the tri-trophic interaction between insects, nematodes and Photorhabdus.
Photorhabdus sp. are entomopathogenic bacteria which, upon experimental infection, interact with the insect immune system, but little is known about the roles of their symbiotic nematode partners Heterorhabditis sp. in natural infections. Here, we investigated the respective contributions of nematodes and bacteria by examining humoral and cellular immune reactions of the model lepidopteran insect Manduca sexta against Heterorhabditis carrying Photorhabdus, nematodes free of bacteria (axenic nematodes) and bacteria alone. Insect mortality was slower following infection with axenic nematodes than when insects were infected with nematodes containing Photorhabdus, or the bacteria alone. Nematodes elicited host immune responses to a lesser extent than bacteria. Transcription of certain recognition and antibacterial genes was lower when insects were naturally infected with nematodes carrying no bacteria compared to insects that received bacteria, either with or without nematodes. Axenic nematodes also did not elicit such high levels of phenoloxidase activity and haemocyte aggregates as did treatments involving Photorhabdus. By contrast, the phagocytic capability of host haemocytes was decreased by both axenic and bacteria-associated nematodes, but not by Photorhabdus alone. These results imply that both bacteria and nematodes contribute separately to the pathogenic modulation of host immune responses during natural infections by the mutualistic Heterorhabdus-Photorhabdus complex.


A mutation in the pericentrin gene causes abnormal interneuron migration to the olfactory bulb in mice.
Precise control of neuronal migration is essential for proper function of the brain. Taking a forward genetic screen, we isolated a mutant mouse with defects in interneuron migration. By genetic mapping, we identified a frame shift mutation in the pericentrin (Pcnt) gene. The Pcnt gene encodes a large centrosomal coiled-coil protein that has been implicated in schizophrenia. Recently, frame shift and premature termination mutations in the pericentrin (PCNT) gene were identified in individuals with Seckel syndrome and microcephalic osteodysplastic primordial dwarfism (MOPD II), both of which are characterized by greatly reduced body and brain sizes. The mouse Pcnt mutant shares features with the human syndromes in its overall growth retardation and reduced brain size. We found that dorsal lateral ganglionic eminence (dLGE)-derived olfactory bulb interneurons are severely affected and distributed abnormally in the rostral forebrain in the mutant. Furthermore, mutant interneurons exhibit abnormal migration behavior and RNA interference knockdown of Pcnt impairs cell migration along the rostal migratory stream (RMS) into the olfactory bulb. These findings indicate that pericentrin is required for proper migration of olfactory bulb interneurons and provide a developmental basis for association of pericentrin function with interneuron defects in human schizophrenia.


Effect of vaccination against sub-clinical Porcine Circovirus type 2 infection in a high-health finishing pig herd: A randomised clinical field trial.
During the last decade, the clinical manifestation of Porcine Circovirus type 2 (PCV2) infections has mostly changed from postweaning multisystemic wasting syndrome and high mortality to sub-clinical infections manifested only through impaired production parameters. However, co-infection with other respiratory pathogens often results in a larger effect on production, sometimes with clinical signs. Little is known about the impact of a moderate level PCV2 infection without co-infections, particularly in terms of feed conversion ratio and antimicrobial consumption. The purpose of the study was to evaluate the effect of vaccination against PCV2 in a sub-clinically infected, high-health finishing herd in terms of viral load in serum, feed conversion ratio and antimicrobial treatments. The study was conducted as a randomised clinical field trial with a parallel group design. Vaccination against PCV2 significantly (p<0.001) reduced the prevalence of PCV2-positive serum pools, from 91% in the control group to 6% in the vaccinated group, as well as the viral load for positive pools from 5.79 to 3.99 log(10) copies per ml serum. Despite this, feed conversion ratio for the two groups were not significantly different with an average of 2.75 and 2.76 feeding units/kg gain for vaccinated and control pigs, respectively (p=0.598). The proportion of pigs treated by injection with an antimicrobial was lower in the vaccinated group (4.4%) compared to the non-vaccinated group (5.6%), but the difference was not significant (p=0.125). In conclusion, in this herd without respiratory co-infections and with moderate viral loads of PCV2, vaccination significantly reduced the prevalence and viral load of PCV2-positive pigs, but had no significant impact on feed conversion ratio or antimicrobial consumption.


Evaluation of quadrivalent HPV 6/11/16/18 vaccine efficacy against cervical and anogenital disease in subjects with serological evidence of prior vaccine type HPV infection.
In the quadrivalent (types 6/11/16/18) HPV vaccine (GARDASIL/SILGARD) clinical program, 73% of women aged 16-26 were naïve to all vaccine HPV types. In these women, prophylactic administration of the vaccine was highly effective in preventing HPV 6/11/16/18-related cervical disease. Of the remaining women, 15% of had evidence of past infection with one or more vaccine HPV types (seropositive and DNA negative) at the time of enrollment. Here we present an analysis in this group of women to determine the efficacy of the HPV 6/11/16/18 vaccine against new cervical and external anogenital disease related to the same vaccine HPV type which had previously been cleared. Vaccine tolerability in this previously infected population was also assessed. 18,174 women were enrolled into 3 clinical studies. The data presented comprise a subset of these subjects (n = 2,617) who were HPV seropositive and DNA negative at enrollment (for >or=1 vaccine type). In each study, subjects were randomized in a 1:1 ratio to receive HPV 6/11/16/18 vaccine or placebo at day 1, month 2 and month 6 (without knowledge of baseline HPV status). Procedures performed for efficacy data evaluation included detailed genital examination, Pap testing, and collection of cervicovaginal and external genital specimens. Analyses of efficacy were carried out in a population stratified by HPV serology and HPV DNA status at enrollment. Subjects were followed for an average of 40 months. Seven subjects in the placebo group developed cervical disease, and eight subjects developed external genital disease related to a vaccine HPV type they had previously encountered. No subject receiving HPV 6/11/16/18 vaccine developed disease to a vaccine HPV type to which they were seropositive and DNA negative at enrolment. These results suggest that natural HPV infection-elicited antibodies may not provide complete protection over time, however the immune response to the HPV 6/11/16/18 vaccine appears to prevent reinfection or reactivation of disease with vaccine HPV types. Vaccine-related adverse experiences were higher among subjects receiving vaccine, mostly due to increased injection site adverse experiences.


Determining K+ channel activation curves from K+ channel currents.
Potassium ion channels are generally believed to have current-voltage (IV) relations which are linearly related to driving force ( V - E(K)), where V is membrane potential and E(K) is the potassium ion equilibrium potential. Consequently, activation curves for K+ channels have often been measured by normalizing voltage-clamp families of macroscopic K+ currents with (V - E(K)), where V is the potential of each successive step in the voltage clamp sequence. However, the IV relation for many types of K+ channels actually has a non-linear dependence upon driving force which is well described by the Goldman-Hodgkin-Katz relation. When the GHK dependence on (V - E(K)) is used in the normalization procedure, a very different voltage dependence of the activation curve is obtained which may more accurately reflect this feature of channel gating. Novel insights into the voltage dependence of the rapidly inactivating I(A) channels Kv1.4 and Kv4.2 have been obtained when this procedure was applied to recently published results.


Interactions between methadone and medications used to treat HIV infection: a review.
It is critical for providers caring for HIV-positive methadone recipients to have accurate information on pharmacologic interactions between methadone and antiretroviral therapy. If providers do not have these data, symptoms of narcotic withdrawal or excess due to medication interactions may be mismanaged, and antiretroviral regimens may be suboptimal in efficacy or associated with increased side effects and toxicities. This review was undertaken to clarify what is known about interactions between pharmacotherapies of opiate dependence and HIV-related medications, to suggest clinically useful approaches to these issues, and to outline areas which need further study. A search for relevant published papers and abstracts presented at scientific meetings was conducted using electronic databases. These documents were obtained and reviewed, and additional publications referenced in them were also reviewed. Pharmacokinetic interactions between methadone and zidovudine, didanosine, stavudine, abacavir, nevirapine, efavirenz and nelfinavir have been documented. The mechanisms, clinical implications and management of these interactions are reviewed. Interactions between methadone and some HIV-related medications are known to occur, yet their characteristics cannot reliably be predicted based on current understanding of metabolic enzyme induction and inhibition, or through in vitro studies. Only carefully designed and conducted pharmacologic studies involving human subjects can help us define the nature of the interactions between methadone (and other pharmacotherapies for opiate dependence) and specific HIV-related medications. Clinicians must be aware of known interactions and be alert to the possibility that interactions which are still undocumented may be present among their patients.


An active membrane model of the cerebellar Purkinje cell II. Simulation of synaptic responses.
1. Both excitatory and inhibitory postsynaptic channels were added to a previously described complex compartmental model of a cerebellar Purkinje cell to examine model responses to synaptic inputs. All model parameters remained as described previously, leaving maximum synaptic conductance as the only parameter that was tuned in the studies described in this paper. Under these conditions the model was capable of reproducing physiological recorded responses to each of the major types of synaptic input. 2. When excitatory synapses were activated on the smooth dendrites of the model, the model generated a complex dendritic Ca2+ spike similar to that generated by climbing fiber inputs. Examination of the model showed that activation of P-type Ca2+ channels in both the smooth and spiny dendrites augmented the depolarization during the complex spike and that Ca(2+)-activated K+ channels in the same dendritic regions determined the duration of the spike. When these synapses were activated under simulated current-clamp conditions the model also generated the characteristic dual reversal potential of the complex spike. The shape of the dendritic complex spike could be altered by changing the maximum conductance of the climbing fiber synapse and thus the amount of Ca2+ entering the cell. 3. To explore the background simple spike firing properties of Purkinje cells in vivo we added excitatory "parallel fiber" synapses to the spiny dendritic branches of the model. Continuous asynchronous activation of these granule cell synapses resulted in the generation of spontaneous sodium spikes. However, very low asynchronous input frequencies produced a highly regular, very fast rhythm (80-120 Hz), whereas slightly higher input frequencies resulted in Purkinje cell bursting. Both types of activity are uncharacteristic of in vivo Purkinje cell recordings. 4. Inhibitory synapses of the sort presumably generated by stellate cells were also added to the dendritic tree. When asynchronous activation of these inhibitory synapses was combined with continuous asynchronous excitatory input the model generated somatic action potentials in a much more stochastic pattern typical of real Purkinje cells. Under these conditions simulated inter-spike interval distributions resembled those found in experimental recordings. Also, as with in vivo recordings, the model did not generate dendritic bursts. This was mainly due to inhibition that suppressed the generation of dendritic Ca2+ spikes. 5. In the presence of asynchronous inhibition, changes in the average frequency of excitatory inputs modulated background simple spike firing frequencies in the natural range of Purkinje cell firing frequencies (30-100 Hz). This modulation was very sensitive to small changes in the average frequency of excitatory inputs.(ABSTRACT TRUNCATED AT 400 WORDS)


Factors Influencing Bacterial Diversity and Community Composition in Municipal Drinking Waters in the Ohio River Basin, USA.
The composition and metabolic activities of microbes in drinking water distribution systems can affect water quality and distribution system integrity. In order to understand regional variations in drinking water microbiology in the upper Ohio River watershed, the chemical and microbiological constituents of 17 municipal distribution systems were assessed. While sporadic variations were observed, the microbial diversity was generally dominated by fewer than 10 taxa, and was driven by the amount of disinfectant residual in the water. Overall, Mycobacterium spp. (Actinobacteria), MLE1-12 (phylum Cyanobacteria), Methylobacterium spp., and sphingomonads were the dominant taxa. Shifts in community composition from Alphaproteobacteria and Betaproteobacteria to Firmicutes and Gammaproteobacteria were associated with higher residual chlorine. Alpha- and beta-diversity were higher in systems with higher chlorine loads, which may reflect changes in the ecological processes structuring the communities under different levels of oxidative stress. These results expand the assessment of microbial diversity in municipal distribution systems and demonstrate the value of considering ecological theory to understand the processes controlling microbial makeup. Such understanding may inform the management of municipal drinking water resources.


Cognitive neuropsychiatric analysis of an additional large Capgras delusion case series.
Although important to cognitive neuropsychiatry and theories of delusions, Capgras delusion has largely been reported in single case studies. Bell et al. [2017. Uncovering Capgras delusion using a large scale medical records database. British Journal of Psychiatry Open, 3(4), 179-185] previously deployed computational and clinical case identification on a large-scale medical records database to report a case series of 84 individuals with Capgras delusion. We replicated this approach on a new database from a different mental health service provider while additionally examining instances of violence, given previous claims that Capgras is a forensic risk. We identified 34 additional cases of Capgras. Delusion phenomenology, clinical characteristics, and presence of lesions detected by neuroimaging were extracted. Although most cases involved misidentification of family members or partners, a notable minority (20.6%) included the misidentification of others. Capgras typically did not present as a monothematic delusion. Few cases had identifiable lesions with no evidence of right-hemisphere bias. There was no evidence of physical violence associated with Capgras. Findings closely replicate Bell et al. (2017). The majority of Capgras delusion phenomenology conforms to the "dual route" model although a significant minority of cases cannot be explained by this framework.


Prevalence and risk factors of child neglect in the general population.
Child neglect is a major public health problem. It is the most frequently reported and substantiated form of maltreatment in youth protective services, and its effects are the most harmful to children. Yet, very few studies have documented its extent and risk factors in the general population. This study aims at documenting the annual prevalence and risk factors of child-neglect behaviours in the general population according to child age and parental gender. Cross-sectional population survey. A sample consisting of 3298 mothers and 1104 fathers of children between six months and 15 years old responded to a telephone survey. The prevalence of neglect was documented using the short version of the Parent-Report Multidimensional Neglectful Behaviour Scale for three child-age categories. Annual prevalence rates vary between 20.6% (95% CI 18.2-23.1) and 29.4% (95% CI 26.6-32.4) depending on the children's age. Although statements do not vary by parent gender, the factors associated with neglect depend on whether they are reported by the mother or the father. Mothers present more mental health problems, while fathers struggle more commonly with difficulties related to their life context. Measuring neglect in the population presents numerous challenges. Nonetheless, this study made it possible to document the extent of neglectful behaviours in the general population. The results confirm that the risk factors related to neglectful behaviours are similar to those documented in studies concerning situations of neglect reported to the authorities. Other studies are needed to better understand how this phenomenon is manifested in the population.


Is metatarsus primus elevatus truly observed in hallux rigidus? Radiographic study using mapping methods.
Hallux rigidus and metatarsus primus elevatus (MPE) are associated, but their causal relationship remains unknown. Several surgical approaches for treating hallux rigidus are available. We evaluated morphological characteristics of hallux rigidus with different grades to determine the optimal surgical approach. The amount of degenerative change in the metatarsophalangeal joint on the preoperative roentgenograms was graded on a scale of 1-3. We analyzed the morphology of hallux rigidus using X-ray image mapping developed by our team. This study involved weight-bearing, dorsoplantar, and lateral foot X-rays of 36 feet from 26 patients underwent surgery for hallux rigidus (Group R) at our institution, and 26 normal feet (Group N). A two-dimensional coordinate system was used to analyze the sharps of these feet by converting each dot on the radiographs into X and Y coordinates. Diagrams of the feet from each group were drawn for comparison. Feet with grades 2 (Group R2) and 3 (Group R3) hallux rigidus and normal feet were compared by Kruskal-Wallis test. Mapping revealed that the tip of distal phalanges of the second, and third toes in Group R medially shifted (P < 0.05) in dorsoplantar image of the feet, and that the medial point, a part of the talus, navicular, cuneiform, and first metatarsal bone in Group R, shifted lower (P < 0.05) in lateral feet images of the feet. Multiple comparisons revealed a significant navicular bone depression in grade 3 hallux rigidus compared with normal feet. A significant difference was observed between Group N and R3 but not between Group R2 and N or R3. X-ray morphological analysis of the foot revealed MPE in Group R. Elevation gradually increased as hallux rigidus grade worsened. Therefore, osteotomy combined with cheilectomy, whereby the first metatarsal bone can be tilted toward the plantar side, are useful for treating a higher-grade hallux rigidus. Level III, comparative study.


Are there gender-related differences in the psychometric properties of the Oswestry Disability Index?
Despite the wide body of research on the properties of the Oswestry Disability Index (ODI), only a few studies have investigated whether ODI scores can be interpreted similarly in both genders. A few previous studies suggested that the ODI may behave differently in different populations, e.g. in different age groups. The objective was to investigate gender-related differences in the psychometric properties of the ODI amongst patients with chronic low back pain. Observational cross-sectional cohort study. University outpatient Physical and Rehabilitation Medicine clinic. Consecutive patients seen in an outpatient Physical and Rehabilitation Medicine clinic at a university hospital between April 2014 and February 2017. Internal consistency was evaluated using Cronbach's alpha. Factor structure was investigated using exploratory factor analysis. Gender-related differences in psychometric properties of ODI items were assessed using item response theory analysis. The study included 912 patients, 579 women (63%), with an average age of 45.8 (SD 14.2) years old. The Cronbach's alpha for both genders was good at 0.88. The discrimination abilities of all 10 ODI items were mostly high to perfect for both men and women with only small fluctuations. The item information function curves were similar for most of the items. Exploratory factor analysis resulted in a unidimensional one-factor structure for both genders. The ODI appears to be a similarly unidimensional and internally consistent questionnaire in both genders without any substantial variability in the items' difficulty and discrimination. The ODI produces psychometrically similar results in both genders. Small and clinically hardly significant gender-related differences in the properties of ODI can be neglected.


Hydrochalarones: a novel endohedral metallofullerene platform for enhancing magnetic resonance imaging contrast.
Targeted imaging requires contrast agents that remain in the vasculature for extended periods of time. A new contrast agent is described in which gadolinium is encapsulated within an extremely stable carbon sphere, thus allowing for safe extended residence. Water solubility and small particle size is achieved with novel fullerene chemistry, attaching multiple oligoethylene glycol groups through nitrogen chemistry. These new compounds can be used to visualize tissue architecture in vivo with standard MRI techniques.


Raised temperatures over the Kericho tea estates: revisiting the climate in the East African highlands malaria debate.
Whether or not observed increases in malaria incidence in the Kenyan Highlands during the last thirty years are associated with co-varying changes in local temperature, possibly connected to global changes in climate, has been debated for over a decade. Studies, using differing data sets and methodologies, produced conflicting results regarding the occurrence of temperature trends and their likelihood of being responsible, at least in part, for the increases in malaria incidence in the highlands of western Kenya. A time series of quality controlled daily temperature and rainfall data from Kericho, in the Kenyan Highlands, may help resolve the controversy. If significant temperature trends over the last three decades have occurred then climate should be included (along with other factors such as land use change and drug resistance) as a potential driver of the observed increases in malaria in the region. Over 30 years (1 January 1979 to 31 December 2009) of quality controlled daily observations ( > 97% complete) of maximum, minimum and mean temperature were used in the analysis of trends at Kericho meteorological station, sited in a tea growing area of Kenya's western highlands. Inhomogeneities in all the time series were identified and corrected. Linear trends were identified via a least-squares regression analysis with statistical significance assessed using a two-tailed t-test. These 'gold standard' meteorological observations were compared with spatially interpolated temperature datasets that have been developed for regional or global applications. The relationship of local climate processes with larger climate variations, including tropical sea surface temperatures (SST), and El Niño-Southern Oscillation (ENSO) was also assessed. An upward trend of ≈0.2°C/decade was observed in all three temperature variables (P < 0.01). Mean temperature variations in Kericho were associated with large-scale climate variations including tropical SST (r = 0.50; p < 0.01). Local rainfall was found to have inverse effects on minimum and maximum temperature. Three versions of a spatially interpolated temperature data set showed markedly different trends when compared with each other and with the Kericho station observations. This study presents evidence of a warming trend in observed maximum, minimum and mean temperatures at Kericho during the period 1979 to 2009 using gold standard meteorological observations. Although local factors may be contributing to these trends, the findings are consistent with variability and trends that have occurred in correlated global climate processes. Climate should therefore not be dismissed as a potential driver of observed increases in malaria seen in the region during recent decades, however its relative importance compared to other factors needs further elaboration. Climate services, pertinent to the achievement of development targets such as the Millennium Development Goals and the analysis of infectious disease in the context of climate variability and change are being developed and should increase the availability of relevant quality controlled climate data for improving development decisions. The malaria community should seize this opportunity to make their needs heard.


Investigations of potential microbial methanogenic and carbon monoxide utilization pathways in ultra-basic reducing springs associated with present-day continental serpentinization: the Tablelands, NL, CAN.
Ultra-basic reducing springs at continental sites of serpentinization act as portals into the biogeochemistry of a subsurface environment with H2 and CH4 present. Very little, however, is known about the carbon substrate utilization, energy sources, and metabolic pathways of the microorganisms that live in this ultra-basic environment. The potential for microbial methanogenesis with bicarbonate, formate, acetate, and propionate precursors and carbon monoxide (CO) utilization pathways were tested in laboratory experiments by adding substrates to water and sediment from the Tablelands, NL, CAD, a site of present-day continental serpentinization. Microbial methanogenesis was not observed after bicarbonate, formate, acetate, or propionate addition. CO was consumed in the live experiments but not in the killed controls and the residual CO in the live experiments became enriched in (13)C. The average isotopic enrichment factor resulting from this microbial utilization of CO was estimated to be 11.2 ± 0.2‰. Phospholipid fatty acid concentrations and δ(13)C values suggest limited incorporation of carbon from CO into microbial lipids. This indicates that in our experiments, CO was used primarily as an energy source, but not for biomass growth. Environmental DNA sequencing of spring fluids collected at the same time as the addition experiments yielded a large proportion of Hydrogenophaga-related sequences, which is consistent with previous metagenomic data indicating the potential for these taxa to utilize CO.


Overcoming challenges in extracting prescribing habits from veterinary clinics using big data and deep learning.
Understanding antimicrobial usage patterns and encouraging appropriate antimicrobial usage is a critical component of antimicrobial stewardship. Studies using VetCompass Australia and Natural Language Processing (NLP) have demonstrated antimicrobial usage patterns in companion animal practices across Australia. Doing so has highlighted the many obstacles and barriers to the task of converting raw clinical notes into a format that can be readily queried and analysed. We developed NLP systems using rules-based algorithms and machine learning to automate the extraction of data describing the key elements to assess appropriate antimicrobial use. These included the clinical indication, antimicrobial agent selection, dose and duration of therapy. Our methods were applied to over 4.4 million companion animal clinical records across Australia on all consultations with antimicrobial use to help us understand what antibiotics are being given and why on a population level. Of these, approximately only 40% recorded the reason why antimicrobials were prescribed, along with the dose and duration of treatment. NLP and deep learning might be able to overcome the difficulties of harvesting free text data from clinical records, but when the essential data are not recorded in the clinical records, then, this becomes an insurmountable obstacle.


On random sample size, ignorability, ancillarity, completeness, separability, and degeneracy: sequential trials, random sample sizes, and missing data.
The vast majority of settings for which frequentist statistical properties are derived assume a fixed, a priori known sample size. Familiar properties then follow, such as, for example, the consistency, asymptotic normality, and efficiency of the sample average for the mean parameter, under a wide range of conditions. We are concerned here with the alternative situation in which the sample size is itself a random variable which may depend on the data being collected. Further, the rule governing this may be deterministic or probabilistic. There are many important practical examples of such settings, including missing data, sequential trials, and informative cluster size. It is well known that special issues can arise when evaluating the properties of statistical procedures under such sampling schemes, and much has been written about specific areas (Grambsch P. Sequential sampling based on the observed Fisher information to guarantee the accuracy of the maximum likelihood estimator. Ann Stat 1983; 11: 68-77; Barndorff-Nielsen O and Cox DR. The effect of sampling rules on likelihood statistics. Int Stat Rev 1984; 52: 309-326). Our aim is to place these various related examples into a single framework derived from the joint modeling of the outcomes and sampling process and so derive generic results that in turn provide insight, and in some cases practical consequences, for different settings. It is shown that, even in the simplest case of estimating a mean, some of the results appear counterintuitive. In many examples, the sample average may exhibit small sample bias and, even when it is unbiased, may not be optimal. Indeed, there may be no minimum variance unbiased estimator for the mean. Such results follow directly from key attributes such as non-ancillarity of the sample size and incompleteness of the minimal sufficient statistic of the sample size and sample sum. Although our results have direct and obvious implications for estimation following group sequential trials, there are also ramifications for a range of other settings, such as random cluster sizes, censored time-to-event data, and the joint modeling of longitudinal and time-to-event data. Here, we use the simplest group sequential setting to develop and explicate the main results. Some implications for random sample sizes and missing data are also considered. Consequences for other related settings will be considered elsewhere.


Retrospective versus original information on physical and psychosocial exposure at work.
Retrospective exposure assessments are often performed in epidemiologic studies. The presence of an eventual misclassification, both nondifferential and differential, is debated but can rarely be investigated. The aim of this study was to compare self-reported information on the same physical and psychosocial work exposures with 25 years' difference. In 1969-1970 a survey of randomly chosen men and women in Stockholm county, concerning, among other things, work exposures, was undertaken. During 1993-1994, 280 subjects participated in a reexamination, regarding psychosocial and physical factors at work and musculoskeletal disorders. The questions were all formulated in the same way as in 1969-1970. When self-reported information on work exposures, collected with a 25-year interval, was compared, acceptable, although not high, agreement was found for 3 out of 4 physical factors and for 4 out of 10 physical environmental factors. Questions measuring psychosocial load had somewhat lower agreement. Current exposure status influenced the memory of past exposures. Study subjects who reported low-back disorders at the reexamination tended to show a better agreement in their assessments of retrospective exposures than those without current symptoms. When relative risks from original and retrospective data were calculated, hardly any influence on the estimates due to that differential misclassification could be found. For persons with and without neck or shoulder symptoms no apparent differences in assessments were found. Retrospective assessments of exposures at the workplace showed misclassifications to a certain degree. However, the influence of the misclassifications on the risk estimates was limited.


Bacterial superantigens mediate T cell deletions in the mouse severe combined immunodeficiency-human liver/thymus model.
The ability to analyze T cell receptor (TCR) thymic repertoire shaping in humans by self and foreign ligands is hampered by the lack of suitable models. We recently documented that the mouse severe combined immunodeficiency (SCID)-human fetal liver/thymus model recapitulates the TCR V beta gene repertoire of human thymocytes. Here, we show that an exogenous superantigen, staphylococcal enterotoxin B, administered to such mice induces clonal deletions in both CD4+8- and CD8+4- cells involving the same human V beta clones that are selected in vitro by this toxin. This model, therefore, may allow comprehensive studies into the effects of microbial and other agents on human T cell thymic selection processes in a biologically relevant setting.


An investigation into the in vivo performance variability of pH responsive polymers for ileo-colonic drug delivery using gamma scintigraphy in humans.
Gastrointestinal performance of tablets coated with pH responsive acrylic polymers (Eudragit) was investigated in human volunteers. Tablet cores were coated with Eudragit S dissolved in ethanol (organic), Eudragit S aqueous dispersion (aqueous), or Eudragit FS aqueous dispersion. Eight fasted volunteers received the tablets in a two-way crossover design-treatment 1: Eudragit S (organic) and Eudragit FS coated tablets; treatment 2: Eudragit S (aqueous) and Eudragit FS coated tablets. Eudragit FS coated tablets were included in both treatments to assess its intra-subject performance. Tablets were radiolabelled and followed by gamma scintigraphy; the disintegration times and positions were recorded. Tablets coated with Eudragit S (aqueous) disintegrated in all volunteers mainly in the proximal to mid small intestine. Eudragit S (organic) tablets failed to disintegrate in three out of eight volunteers, while disintegration was in the ileo-caecal junction and ascending colon in all others. Eudragit FS coated tablets disintegrated in 14 out of the 16 administrations. The Eudragit FS coated tablets that did disintegrate exhibited consistent intra- and inter-subject performance, with the site of disintegration focused on the ileo-caecal junction and ascending colon. These in vivo results correlate better with our published in vitro dissolution data in physiological bicarbonate buffers compared to phosphate buffers.


Congenital hypothyroidism simulating acromegaly - a diagnostic pitfall.
Since introduction of population-based neonatal screening for congenital hypothyroidism (CH), cases of long-term untreated inborn hypothyreosis have become very rare whereas its clinical symptoms are currently not well known. We report a patient with CH due to an ectopic thyroid. The presented case is exceptional due to both advanced age of diagnosis and unusual clinical presentation, as the anomaly was detected during evaluation of suspected acromegaly at the age of 62. This report indicates that there is still necessity of considering, in spite of its rarity, congenital form in differential diagnosis of hypothyroidism.


Specific functional and immunologic assay of plasma plasminogen in hereditary angioedema, in hereditary angioedema treated with tranexamic acid, and in normal subjects.
Plasma plasminogen levels were determined by a specific esterolytic assay and a radial immunodiffusion assay, both of which were standardized on a weight basis by using highly purified plasminogen diluted in plasminogen-free plasma. In thirteen normal individuals the functional and antigenic levels were 275 +/- 61 microgram/ml and 285 +/- 61 microgram/ml, respectively (r = 0.95), whereas in 58 plasmas from individuals with hereditary angioedema the levels were 272 +/- 58 microgram/ml and 265 +/- 64 microgram/ml, respectively (r = 0.89). In two patients treated with tranexamic acid either acutely or chronically, both the functional and antigenic plasminogen levels were diminished.


Characterization of immunotoxins active against ovarian cancer cell lines.
The purpose of the present study was to develop immunotoxins directed against human ovarian carcinoma cells. Four monoclonal antibodies (260F9, 454C11, 280D11, and 245E7) were chosen because they were found to bind to various ovarian carcinoma cell lines. These antibodies were covalently linked to either Pseudomonas exotoxin (PE) or ricin A chain (RTA), and the conjugates were tested against five ovarian cancer cell lines (OVCAR-2, -3, -4, -5; A1847). The ability of the immunotoxins to inhibit both protein synthesis and colony formation was evaluated. Qualitatively similar results were obtained for both types of assays. Usually, PE conjugates were more toxic than their corresponding RTA conjugates. 454C11-PE was very toxic for all ovarian carcinoma lines, whereas 454C11-RTA had low activity. Both 260F9-PE and 260F9-RTA were active in all OVCAR cell lines but not in A1847 cells. 280D11-PE was toxic for OVCAR-4; otherwise, 280D11-PE and RTA conjugates of both 280D11 and 245E7 had little activity. Specificity of immunotoxin action was shown by competition by excess antibody, nontoxicity in nontarget cells, and inactivity of an irrelevant immunotoxin. To investigate the basis of antibody-dependent differences in activity of the various immunotoxins, antibody uptake was studied in OVCAR-2 cells, and the results indicate that antibody internalization is one important factor in the activity of immunotoxins.


A simple diagnostic test to confirm correct intravascular placement of peripheral catheters in order to avoid extravasation.
Intravenous catheters are ubiquitous among modern medical management of patients, yet misplaced or tissued cannulas can result in serious iatrogenic injury due to infiltration or extravasation of injectate. Prevention is difficult, and currently few reliable tests exist to confirm intravascular placement of catheters in awake spontaneously breathing patients. Twenty conscious spontaneously breathing healthy volunteers were injected with 50 mL normal saline and 50 mL 4.2%, or 50 mL 2.1%, or 20 mL 4.2% sodium bicarbonate in a random order. A blinded anesthetist observed continuous sampling of exhaled carbon dioxide and was asked to differentiate between the sodium bicarbonate and saline injections. Peak increase in measured exhaled carbon dioxide was also calculated. Exhaled carbon dioxide increased significantly in participants injected with intravenous sodium bicarbonate. Mean peak increase was 7.4 mm Hg (±2.1 mm Hg) for 50 mL 4.2% sodium bicarbonate, 4.7 mm Hg (±2.5 mm Hg) for 20 mL 4.2% sodium bicarbonate, and 3.5 mm Hg (±1. 8 mm Hg) for 50 mL 2.1% sodium bicarbonate. The blinded observer correctly identified the injection as sodium bicarbonate or normal saline in every instance. Intravenous injection of dilute sodium bicarbonate with exhaled carbon dioxide monitoring reliably confirms correct intravascular placement of a catheter. A transient increase of exhaled carbon dioxide by 10% or more is an objective and reliable confirmation of intravascular location of the catheter. We recommend using 20 mL of 4.2% sodium bicarbonate to minimize the mEq dose of sodium bicarbonate required.


Endoplasmic reticulum stress contributes to aortic stiffening via proapoptotic and fibrotic signaling mechanisms.
Vascular smooth muscle cell apoptosis and collagen synthesis contribute to aortic stiffening. A cellular signaling mechanism contributing to apoptotic and fibrotic events is endoplasmic reticulum (ER) stress. In this study, we tested the hypothesis that induction of ER stress in a normotensive rat would cause profibrotic and apoptotic signaling, thereby contributing to aortic stiffening. Furthermore, we hypothesized that inhibition of ER stress in an angiotensin II (Ang II) model of hypertension would improve aortic stiffening. Induction of ER stress with tunicamycin in normotensive Sprague-Dawley rats (10 μg/kg per day, osmotic pump, 28 days) caused an increase in systolic blood pressure (mm Hg; 160±5) compared with vehicle-treated (127±3) or tunicamycin-treated rats that were cotreated with ER stress inhibitor 4-phenylbutyric acid (100 mg/kg per day, 28 days, [124±6]). There was an increase in aortic apoptosis (fold; 3.0±0.3), collagen content (1.4±0.1), and fibrosis (2.0±0.1) in the tunicamycin-treated rats compared with vehicle-treated rats. Inhibition of ER stress in male Sprague-Dawley rats given Ang II (60 ng/min, osmotic pump, 28 days) and treated with either tauroursodeoxycholic acid or phenylbutyric acid (100 mg/kg per day, i.p., 28 days) led to a 20 mm Hg decrease in blood pressure with either inhibitor compared with Ang II treatment alone. Aortic apoptosis, increased collagen content, and fibrosis in Ang II-treated rats were attenuated with ER stress inhibition. We conclude that ER stress is a new signaling mechanism that contributes to aortic stiffening via promoting apoptosis and fibrosis.